ABSTRACT Systemic sclerosis is an autoimmune disease, characterized by progressive fibrosis of the skin and internal organs. There is currently no FDA-approved agent to prevent the progression of fibrosis in systemic sclerosis. The pathogenesis of systemic sclerosis involves a complex interplay of abnormalities of the immune system, blood vessels and fibroblasts. One well-studied mechanism of fibrosis in systemic sclerosis consists of the excessive activation of the transforming growth factor beta (TGFbeta) signaling pathway in fibroblasts, which leads to excessive collagen deposition and transformation of fibroblasts in alpha-smooth muscle actin- expressing myofibroblasts. Our laboratory focuses on protein tyrosine phosphatases, enzymes that control signal transduction by removing phosphate from phosphorylated tyrosines, thus balancing the action of protein tyrosine kinases. The role of tyrosine phosphatases in systemic sclerosis has remained mostly unaddressed. This project stems from the observation that a tyrosine phosphatase called PTP4A1 is overexpressed in dermal fibroblast from systemic sclerosis patients and plays a pro-fibrotic function in fibroblasts ex vivo and in vivo. Mechanistically, PTP4A1 promotes TGFbeta signaling by forming a complex with SRC that inhibits basal SRC auto-phosphorylation and degradation. The objectives of this grant proposal are to dissect the molecular details of the PTP4A1-SRC complex (Aim 1), and to validate PTP4A1 as a key player in SSc fibrosis via experimentation in mice (Aim 2) and further assessment of SSc clinical specimens (Aim 3). The long-term goal is to validate PTP4A1 and/or its downstream pathway as possible targets to prevent and treat fibrosis in systemic sclerosis.